tbuckley/cabot-search huggingface dataset:
Abstract 3743: Genome-wide profiling of DNA N6-methylation from a breast cancer and a matched normal cell lines
Authors: Chunlin Xiao, Valerie Schneider
Journal: Cancer Research (2022)

Abstract DNA N6-methyladenine (m6A) modification has been found widely presented in the human genome, and genome-wide DNA methylation profiling in cancer may reveal epigenetic signatures with significant clinical outcomes. Whole genome sequencing data from PacBio single-molecule real-time (SMRT) system provides signals for identifying the presence of m6A in human genomic DNA. We identified 343,199 m6A modification sites with an average density of 122 per Mb in the HCC1395 breast cancer cell line, whereas 722,303 m6A modification sites with average density of 257 per Mb were observed in a matched normal HCC1395BL cell line, meaning that the total number and the average density of m6A methylation sites in the cancer cell line were reduced more than 50% than that in normal cell line. Only small fraction of the methylation sites was found to be shared between the two cell lines, indicating that significant de-methylation (loss) and new methylation (gain) events occurred in HCC1395 cancer cells. A broad distribution of m6A methylation sites across autosomal chromosomes was observed, but the density of m6A methylation sites on chromosome X was extremely low for both HCC1395 and HCC1395BL cell lines. In contrast, the m6A densities on chromosome 7 and chromosome 22, particularly on their q-arms, from HCC1395 were substantially higher (hypermethylation) than other autosomal chromosomes, suggesting that copy number variations may be associated with these chromosomal regions. Most of the m6A methylation sites were located in intergenic and intronic regions, whereas only about 2~3% of the m6A methylation sites were situated in exonic regions, and 12% on ncRNAs. Understanding the genome-wide distinction of DNA methylation between cancer and matched normal cell lines makes it possible to ask more targeted questions and further investigate the role of methylation in cancer. Citation Format: Chunlin Xiao, Valerie Schneider. Genome-wide profiling of DNA N6-methylation from a breast cancer and a matched normal cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3743.
Abstract 5667: EZH2 inhibition targets B7-H3 in Myc amplified medulloblastoma
Authors: Katherine Shishido, Sujatha Venkataraman, Rajeev Vibhakar, Kiran Velpula, Swapna Asuthkar
Journal: Cancer Research (2022)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The most aggressive MB subtype Group 3, is characterized by Myc amplifications. However, targeting Myc has proven unsuccessful, necessitating alternative therapies for MB. The histone methyltransferase, enhancer of zeste homolog 2 (EZH2), is well-known for its role in catalyzing the tri-methylation of H3K27 (H3K27me3). Recent studies have demonstrated that EZH2 is overexpressed in Group 3 MB and that Myc and EZH2 regulate the expression of the B7 homolog 3 (B7-H3). As we previously showed the oncogenic functions of B7-H3 in Group 3 MB, this study aims to investigate the efficacy of EZH2 inhibition to reduce B7-H3 levels in an effort to improve treatment options and patient survival. Datamining studies conducted using MB patient datasets showed a positive correlation between EZH2 and B7-H3 transcripts. Additionally, we showed that inhibition of EZH2 using EPZ005687 in Myc-amplified MB cell lines downregulated B7-H3 and Myc expression. Furthermore, targeting EZH2 through shRNA and pharmacological inhibition reduced the viability and augmented apoptosis, as indicated by LDH, MTT, clonogenic, and FACS assays. We additionally tested the consequences of EZH2 inhibition on the C17.2, murine neural stem cells, and C17.2 NSC transformed with EZH2 oncogene (C17.2_EZH2OX). Furthermore, the C17.2_EZH2OXcells were susceptible to EPZ005687 treatment compared to C17.2 control cells, as demonstrated by MTT and FACS. Collectively, our study highlights the therapeutic benefits of targeting EZH2 in Myc-amplified MB cell survival. Citation Format: Katherine Shishido, Sujatha Venkataraman, Rajeev Vibhakar, Kiran Velpula, Swapna Asuthkar. EZH2 inhibition targets B7-H3 in Myc amplified medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5667.
Abstract 2531: a
Authors: Adarsh Rajesh, Aaron Havas, Siva Karthik Varanasi, Katrina Evans, Bassem B. Cheikh, Clemens Duerrschmid, Najiba Mammadova, Peter Adams, Susan Kaech
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is an emerging health crisis due to rapidly increasing incidence rates and an overall 5-year survival rate of 18%. Consequently, there is an urgent need for new therapies and better preventive strategies. Aging and obesity are two of the biggest risk factors for HCC, and with ever-increasing aging and obese populations, uncovering how aging and obesity drive the increased risk for HCC has become imperative. Aging and obesity are well known to be characterized by immune dysregulation leading to persistent inflammation, and a dysregulated immune microenvironment is also a common theme shared by multiple hallmarks of HCC. In this study, we aim to assess the immune microenvironment of aged and obese mouse livers by performing spatial phenotyping of distinct immune signatures which can potentially predispose hepatocytes to HCC. To address this, we used Akoya’s ultra-high multiplexed CODEX (CO-Detection by indEXing) imaging system to interrogate 31 different biomarkers in liver samples at the single cell level. Specifically, we compared the liver immune microenvironment of mice within 2 different treatment groups (old mice on a high fat diet (HFD) and young mice on a normal diet (ND)) to the immune landscape of liver tumor tissue. Our goal is to identify distinct immune phenotypes present in both, liver tumor tissues and livers of HFD mice, compared to ND livers - to better understand how immune dysregulation can predispose an aged and obese liver to HCC. Citation Format: Adarsh Rajesh, Aaron Havas, Siva Karthik Varanasi, Katrina Evans, Bassem B. Cheikh, Clemens Duerrschmid, Najiba Mammadova, Peter Adams, Susan Kaech. a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2531.
Abstract 3171: ARL2 is required for homologous recombination repair and colon cancer stem cell maintenance
Authors: Seok Gyeong Choi, Hani Lee, Sojung Ha, Sukjoon Yoon, Woo-Young Kim
Journal: Cancer Research (2022)

Abstract ARL2 is a small GTP binding protein mediates many cytosolic functions including localization of Ras, dynamics of microtubule and fission of mitochondria but its nuclear function is not well elucidated yet. Here we present the novel role of ARL2 in human cancer nucleus and cancer stem cells (CSC). The cancer tissue gene expression data in The Human Protein Atlas and The Cancer Genome Atlas showed possible pro-cancer and nuclear role of ARL2 in colon cancers. The single cell RNA seq analysis suggests its function in colon stem cells. The activation mutant of K-Ras harboring colon cancer cells expressed less ARL2 than the wild type cells but increased ARL2 expression in CSC spheres. The deprivation of ARL2 in colon cancer cell lines using RNAi preferentially eliminated the CSC spheres while it resulted in minimal impact on bulk cultured cell (BCC) numbers. Suppression of ARL2 halted the BCC at M phase as expected but did not change cell cycle in CSC spheres. However, it led to accumulation of a DNA double strand break marker and apoptosis only in CSC spheres which suggest that ARL2’s requirement for double strand DNA break repair in CSC. Out of 6 somatic RAD51 family genes which all mediate the critical early events of homologous recombination repair (HRR), 5 showed significant and positive association with ARL2 in gene expression in human colon cancer tissue suggesting functional link between ARL2 and HRR. Indeed, ARL2 was required for HRR when double strand DNA breaks were induced. These data collectively showed that ARL2 may contribute to the HRR in the nucleus and the ARL2 mediated HRR is more critical for colon CSC survival. Citation Format: Seok Gyeong Choi, Hani Lee, Sojung Ha, Sukjoon Yoon, Woo-Young Kim. ARL2 is required for homologous recombination repair and colon cancer stem cell maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3171.
Childhood encephalitis in the Greater Mekong region (the SouthEast Asia Encephalitis Project): a multicentre prospective study
Authors: Jean David Pommier, Chris Gorman, Yoann Crabol, Kevin Bleakley, Heng Sothy, Ky Santy, Huong Thi Thu Tran, Lam Van Nguyen, Em Bunnakea, Chaw Su Hlaing, Aye Mya Min Aye, Julien Cappelle, Magali Herrant, Patrice Piola, Bruno Rosset, Veronique Chevalier, Arnaud Tarantola, Mey Channa, Jerome Honnorat, Anne Laure Pinto, Sayaphet Rattanavong, Manivanh Vongsouvath, Mayfong Mayxay, Sommanikhone Phangmanixay, Khounthavy Phongsavath, Ommar Swe Tin, Latt Latt Kyaw, Htay Htay Tin, Kyaw Linn, Thi Mai Hung Tran, Philippe Pérot, Nguyen Thi Thu Thuy, Nguyen Hien, Phuc Huu Phan, Philippe Buchy, Philippe Dussart, Denis Laurent, Marc Eloit, Audrey Dubot-Pérès, Olivier Lortholary, Xavier de Lamballerie, Paul N Newton, Marc Lecuit, Philippe Buchy, Em Bunnakea, Julien Cappelle, Mey Channa, Veronique Chevalier, Yoann Crabol, Xavier de Lamballerie, Audrey Dubot-Pérès, Philippe Dussart, Marc Eloit, Chris Gorman, Magali Herrant, Nguyen Hien, Chaw Su Hlaing, Jérôme Honnorat, Tran Thi Mai Hung, Tran Thi Thu Huong, Latt Latt Kyaw, Nguyen Van Lam, Denis Laurent, Marc Lecuit, Kyaw Linn, Olivier Lortholary, Mayfong Mayxay, Aye Mya Min Aye, Paul Newton, Philippe Perot, Sommanikhone Phangmanixay, Khounthavy Phongsavath, Phan Huu Phuc, Anne-Laurie Pinto, Patrice Piola, Jean-David Pommier, Sayaphet Rattanavong, Bruno Rosset, Ky Santy, Heng Sothy, Arnaud Tarantola, Nguyen Thi Thu Thuy, Htay Htay Tin, Ommar Swe Tin, Manivanh Vongsouvath, Pham Nhat An, Dang Duc Anh, Pascal Bonnet, Kimrong Bun, Danoy Chommanam, Viengmon Davong, Patrice Debré, Jean-François Delfraissy, Christian Devaux, Anousone Douangnouvong, Veasna Duong, Benoit Durand, Chanreaksmey Eng, Catherine Ferrant, Didier Fontenille, Lukas Hafner, Le Thanh Hai, Do Thu Huong, Marc Jouan, May July, Magali Lago, Jean-Paul Moatti, Bernadette Murgue, Khin Yi Oo, MengHeng Oum, Khansoudaphone Phakhounthong, Anh Tuan Pham, Do Quyen, Malee Seephonelee, Maud Seguy, Bountoy Sibounheunang, Kanarith Sim, Luong Minh Tan, Cho Thair, Win Thein, Phung Bich Thuy, Hervé Tissot-Dupont, Malavanh Vongsouvath
Journal: The Lancet Global Health (2022)

Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients' conditions.
Abstract 272: Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability
Authors: Sanne Bootsma, Mark P. Dings, Leandro Ferreira Moreno, Kristiaan J. Lenos, Louis Vermeulen, Maarten F. Bijlsma
Journal: Cancer Research (2022)

Abstract In colorectal cancer, peritoneal metastases (PMs) associate with severe morbidity and dismal prognosis. Given the incidence of this disease and the lack of adequate treatments currently available, PMs pose a large unmet clinical need. Although PMs can be accompanied by more widespread metastatic disease, it often occurs as the only sign of dissemination. This implies that the route of metastatic spread to the peritoneum differs from that to distant organs. PMs are thought to result from cancer cells that spill into the abdominal cavity, and are able to attach to the peritoneal lining and form tumor deposits. This cascade places specific demands on the cancer cells. Here, we report that colorectal cancers that present with PMs almost universally classify as consensus molecular subtype 4 (CMS4). This previously recognized disease entity is characterized by mesenchymal features, poor prognosis, and resistance to therapies currently used against peritoneal metastases, which explains their limited efficacy. By leveraging disease models that capture CMS4-specific features, including the ability to form PMs in vivo, we identified elesclomol as a highly effective agent. Elesclomol kills cancer cells in a copper-dependent fashion by targeting the oxidative phosphorylation machinery, which we found to be a specific vulnerability of CMS4 cancers. Elesclomol-Cu2+ was effective following only minutes of exposure to CMS4 cell lines and organoids, supporting its use in intra-abdominal treatment procedures. It is therefore a promising candidate for the local treatment of peritoneal metastases of colorectal cancer. Citation Format: Sanne Bootsma, Mark P. Dings, Leandro Ferreira Moreno, Kristiaan J. Lenos, Louis Vermeulen, Maarten F. Bijlsma. Effective treatment of colorectal peritoneal metastases by exploiting a molecular subtype specific vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 272.
Abstract 4175: Combining a novel MEK inhibitor with immunomodulation to promote an anti-tumor response
Authors: Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Nezar Mehanna, Neal Rosen, Taha Merghoub, Jedd Wolchok
Journal: Cancer Research (2022)

Abstract To enhance the therapeutic scope of MEK inhibitors (MEKis), we aim to develop new strategies to extend their usage to MEKi resistant RAS mutant cancers, which represent an unmet clinical need. CH5126766 (CKI27) binds the allosteric site of MEK to inhibit its kinase activity but is novel due to its interaction with MEK S218 and 228, which blocks their phosphorylation by RAF. CKI27 bound MEK binds to RAF and cannot be released by phosphorylation, thus becoming a dominant negative inhibitor of RAF activation. This prevents the induction of MEK phosphorylation observed with other MEKis. Although this results in more potent tumor control, CKI27 is also capable of inhibiting T cell function because the MAPK/ERK pathway is activated downstream of T cell receptor signaling. We aim to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. We observed that CKI27 increased MHC expression on tumor cells and improved T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity. Intermittent administration of CKI27 allowed T cells to recover and partially relieved these inhibitory effects. Further combination with agonist antibodies anti-OX40 and GITR completely alleviated T cell inhibition and increased combination efficacy with immune checkpoint blockade antibody anti-CTLA-4. We also observed an increase in proliferation and T cell activation markers in LLC tumor bearing mice treated with the combination of CKI27, anti-GITR, and anti-CTLA-4. Understanding the immunomodulatory effects of combining CKI27 with immunotherapy will elucidate the mechanism behind this increased efficacy. This will allow us to make more informed decisions in dosing regimens, overcoming resistance, and generating long-term immune responses in future clinical trials treating patients with RAS mutant cancers. Citation Format: Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Nezar Mehanna, Neal Rosen, Taha Merghoub, Jedd Wolchok. Combining a novel MEK inhibitor with immunomodulation to promote an anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4175.
Abstract 112: Epac signaling facilitates malignant transformation of melanocytes
Authors: Mithalesh Kumar Singh, Sarah Altameemi, Marcos Lares, Shreyans Sadangi, Vijayasaradhi Setaluri
Journal: Cancer Research (2022)

Abstract Cyclic AMP (cAMP) signaling plays a critical role in melanocyte proliferation and differentiation. However, the role of cAMP signaling in malignant transformation of human melanocytes and initiation of melanoma is not fully understood. Previously, we demonstrated that cAMP signaling plays opposite roles in primary and metastatic melanoma cells, i.e., pro- and anti-proliferative roles, respectively. This switch in cAMP action is mediated by the alternative cAMP signaling axis involving EPAC-RAP1 (exchange protein directly activated by cyclic AMP-Ras-related protein 1). In this study, we tested the hypothesis that activation of EPAC signaling is an early event in malignant transformation of melanocytes and is required for survival and proliferation of malignant melanocytes. Here, we show that shRNA-mediated knockdown of PTEN alone or PTEN-KD with lentiviral transduction with BRAF(V600E) results in upregulation of EPAC expression and activation of RAP1 (i.e., RAP1-GTP) in human primary melanocytes. Interestingly, activation of phosphoinositide 3-kinase (PI3K) signaling alone is sufficient for stimulation of maximal EPAC expression as well as proliferation suggesting that EPAC activation is an early event associated with loss of PTEN and melanoma tumor initiation. Inhibition of EPAC activity by either EPAC 1/2 or EPAC2-selective inhibitors suppressed the growth of transformed melanocytes by inhibiting cell cycle progression as evident by downregulation of cyclins E, -A2 and -B1. Inhibition of EPAC signaling also increased cells expressing senescence-associate beta galactosidase activity suggesting that EPAC may contribute to the senescence escape mechanisms in BRAF(V600E) melanocytes. Our data suggest that activation of PI3K pathway alone or in combination with mitogen-activated protein kinase pathway activates EPAC signaling in melanocytes. Since primary but not metastatic melanoma cells remain dependent on EPAC signaling, understanding the mechanisms of action EPAC can open new avenues to prevent melanomagenesis and inhibit melanoma tumor progression. Citation Format: Mithalesh Kumar Singh, Sarah Altameemi, Marcos Lares, Shreyans Sadangi, Vijayasaradhi Setaluri. Epac signaling facilitates malignant transformation of melanocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 112.
Abstract 2423: A Cdh3 - Lam332 signaling axis by a unique subset of leader cells controls breast tumor organoid protrusion dynamics and directed collective migration
Authors: Yanyang Cao, Priscilla Y. Hwang, Maria Clarke, Jose Almeida, Amit Pathak, Gregory D. Longmore
Journal: Cancer Research (2022)

Abstract Carcinoma dissemination can occur when heterogeneous tumor and tumor stromal cells clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and interact with the microenvironment to direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system that mimics the native breast tumor microenvironment, we developed 3D computational models. These hypothesize that for leader cells to polarize to the leading edge and lead directed collective migration they need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance. From scRNAseq of migrating primary tumor organoids, we identify significant K14+ “leader” cell heterogeneity that differs depending upon the environmental signal. We isolate a unique Cadherin-3 (Cdh3) positive leader cell subpopulation that is necessary and sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through controlling the local production of Laminin-332 which is required for integrin/focal adhesion function. Loss of Cdh3 expression in mouse and human primary breast tumor organoids and invasive breast tumor cell lines significantly impairs directed collective migration. In the absence of leader cell Cdh-Cdh3 intercellular adhesions there is reduced cellular β-catenin levels and Laminin 332 production. In syngeneic, orthotopic transplant mouse models, Cdh3 depletion in tumor cells resulted in decreased laminin 332 production at the invasive edge of primary tumors and decreased lung metastasis. Chromatin Immunoprecipitation experiments revealed that in contacted cells β-catenin and TCF4 are present on Lam α3, β3, and γ2 promoter regions. Laminin 332 production by leader cells was required for optimal Integrin/FA function and cellular protrusion stability. These results indicated that in leader cells local Cdh3-Cdh3/β-catenin regulated Laminin 332 production controls protrusion dynamics and overcomes resistance to ECM to lead directed collective tumor migration. Our findings highlight how a unique subset of leader cells in breast tumors interact with the microenvironment to direct collective migration. Citation Format: Yanyang Cao, Priscilla Y. Hwang, Maria Clarke, Jose Almeida, Amit Pathak, Gregory D. Longmore. A Cdh3 - Lam332 signaling axis by a unique subset of leader cells controls breast tumor organoid protrusion dynamics and directed collective migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2423.
Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave
Authors: Mette Holm, Laura Espenhain, Jonathan Glenthøj, Lisbeth Samsø Schmidt, Sannie Brit Nordly, Ulla Birgitte Hartling, Ulrikka Nygaard
Journal: JAMA Pediatrics (2022)

Multisystem inflammatory syndrome in children (MIS